Here, we have presented a selection of 8 projects representing important biomedical research in the areas of reproductive biology, cancer biology, heart disease and transplant rejection, among others. While these projects arise from disparate areas of science and medicine, each project cannot be performed optimally with the technology available at this point in time. These projects drive the Technology Research and Development projects of the National Resource for Translational and Developmental Proteomics (NRTDP) forward ? giving them a tangible and quantifiable goal with the overarching goal to impact and improve human health. Our TR&D projects focus on specific technologies throughout the progression of a proteomics experiment from separations to instrumentation and informatics. Integrating parts of each TR&D, we have arranged our eight Driving Biomedical Projects around four themes. Theme 1. Small Samples and Separations. Top-Down Proteomics of the Oocyte Secretome and Nuclear Proteome and Proteomics of p53 Modification Codes. Theme 2. Targeted Top-Down Proteomics. Top-Down Proteomics of HDL Particles in Atherosclerosis and Using Top-Down Mass Spectrometry to Detect, Quantify, and Isotype Monoclonal Immunoglobulins in Serum. Theme 3. Discovery Translational Proteomics. Predicting Allograft Outcomes Using High-Throughput Whole Protein Analysis and Top-Down Proteomics of Chronic Lymphocytic Leukemia. Theme 4. Epiproteomics. Histone Modification Dynamics in Heart Failure and Histone Modifications in Acute Myeloid Leukemia. It is through the integrated development of next generation proteomics technologies that we will be able to achieve success in these Driving Biomedical Projects. As these projects progress throughout the lifetime of the grant, they will be reassessed and once technologies are matured, will be translated into a Collaboration and Service project, allowing new biomedical problems to drive the next generation of technology.